Dual Protection

New Treatments for Patients with Heart and Kidney Disease

Kidney experts with insight: Professor Frank Eitner and his colleague Gerda Grusdat examine the tissue of patients with kidney disease in a special pneumatic-suspension fluorescence microscope. However, their work on new therapies focuses not just on details but also on the interactions between the kidneys and other organs like the heart.

A weak heart damages the kidneys – and weak kidneys damage the heart. Successful treatments therefore have to incorporate several strategies. With new substances currently under development, researchers atBayer HealthCare are now protecting both organs at the same time.

Story check

Challenge: Heart and kidneys are closely interrelated. Treatments for one organ must also take the other into account.

Solution: Cardiologists and nephrologists are working side by side at BayerHealthCare to develop new treatments for heart and kidney failure.

Benefits: The researchers are also experimenting with dosage forms, hoping to replace injections with tablets, for example.

They are inseparable: heart and kidneys. If either organ is ailing, the other is also affected. “Kidney patients are already at increased risk of developing cardiovascular disease even before they are aware of their kidney damage,” explains Professor Frank Eitner, Head of Kidney Diseases Research at BayerHealthCare in Wuppertal. The bean-shaped organs are the human body’s waste treatment unit: the kidneys filter toxins from the blood, regulate the fluid and electrolyte balance and adjust blood pressure. If they stop working properly, the entire body soon suffers, setting in motion a dangerous downward spiral. Fluid accumulates in the lung, for example. This impedes the exchange of gases, with ever-decreasing amounts of oxygen reaching the blood. This causes the heart to pump flat out – “and in the long run this leaves its mark,” says Eitner. The efficiency of this living pump declines. This, in turn, has repercussions on the kidneys: they are less well supplied with blood and their function is further weakened.

Thorough filters: the kidneys each consist of about 1,000,000 renal corpuscles. The capillary tufts shown here are called glomeruli. Their function is to filter waste products from the blood. After reabsorption of other substances elsewhere in the kidney, the liquid is transported to the bladder as urine.

180 liters

of urine per day are produced in the kidneys.

Filtering Organs

180 liters of urine per day are produced in the kidneys. From this “primary urine”, however, the organs reabsorb water and key substances such as amino acids – the smaller building blocks of proteins. Since this makes the urine more concentrated, we then only excrete around one and a half liters of urine.

Heart and Kidneys Are Inseparable: If Either Organ Is Ailing, the Other Is also Affected

The onset of kidney diseases usually occurs without specific symptoms or pain. Doctors can test the function of the kidneys by measuring markers in the urine as well as in the blood. Based on such markers, kidney patients can be divided into categories with mildly, moderately or severely decreased kidney function. Common reasons for the development of chronic kidney disease are diabetes, high blood pressure and inflammation. The most advanced stage of chronic kidney disease, end-stage renal disease, requires dialysis or transplantation of a kidney. Dialysis treatment enables the survival of such patients by remov ing fluids as well as toxins. However, dialysis patients pay a high price for this survival: their overall life expectancy is dramatically shortened. The main reason for the increased mortality of dialysis patients is the dramatic increase in cardiovascular diseases. But patients suffering from chronic heart failure likewise frequently develop a slow, but steady decline of kidney function.

A Medical Balancing Act in Treatment Necessitates Expertise in Two Specialist Disciplines

Researchers at Bayer are therefore seeking new treatment options for cardiovascular diseases – with the focus on patients with kidney disease. To this end, Eitner is working closely with Professor Stefan Schäfer from the Department of Experimental Medicine for Cardiovascular Diseases and Hematology atBayer HealthCare in Wuppertal. “We are today confronted with a group of patients that is very difficult to treat, patients with both heart failure and kidney failure,” he says. The researchers need to have a precise understanding of the functions of both organs, and these two Bayer scientists and medical doctors are the embodiment of such expertise on the inseparable duo, as they are well aware of the difficulties involved with kidney and heart patients from their times in clinical practice: Eitner is specialized in internal medicine and nephrology, while Schäfer is a specialist in internal medicine and cardiology.

The kidneys filter toxins out of the blood, regulate the water and electrolyte balance and adjust the blood pressure. If they are not functioning correctly, it has repercussions throughout the body. The graphic shows the main causes of chronic kidney failure.

Medical treatment becomes a delicate balancing act, particularly when both heart and kidneys are weakened. “Some standard treatments for heart patients have severe side effects in patients with kidney disease,” explains Eitner. Special medicines known as mineralocorticoid receptor (MR) antagonists for the treatment of chronic heart failure are a case in point. They increase the body’s excretion of sodium and consequently also of fluids. The fluid content of the blood decreases, as does the blood volume. This results in a drop in blood pressure, which relieves the strain on the heart. At the same time, however, particularly patients suffering from chronic kidney disease are at increased risk for accumulation of potassium in the blood. An excess of this sensitive electrolyte can lead to dangerous disturbances of the heart’s rhythm. “Hyperkalemia can become life-threatening within hours,” explains Eitner. The doctors must therefore weigh up the situation carefully and closely monitor patients treated with this class of drugs. Heart patients with kidney disease are often excluded out of hand. The dilemma, says Eitner, is that “fewer than half of the heart patients who are in need of the drug actually receive it.”

Fewer than half of the heart patients who are in need of the drug actually receive it.

Prof. Frank Eitner, Head of Kidney Diseases Research at Bayer HealthCare

One new candidate from Bayer’s research for patients with heart and kidney diseases is a new MR antagonist. Bayer scientists have optimized the active substance in such a way that it provides effective protection against chronic heart and kidney injury yet minimizes the risk of electrolyte disturbances. A first clinical study in heart failure patients with chronic kidney disease proved that this novel MR antagonist influences blood potassium levels within the therapeutic range to a much lesser extent. Clinical studies have just been started globally to assess the safety and efficacy of the novel MR antagonist.

Another example from Bayer‘s active substance research program is the treatment of renal anemia, a condition that is common in patients with advanced stages of chronic kidney disease. “The current treatment may damage the heart,” explains Schäfer. This is because the kidneys measure and regulate the oxygen content of the blood. If the blood contains too little oxygen, the kidney secretes the hormone erythropoetin - or EPO for short. This hormone activates production in the bone marrow of red blood cells, the carriers of oxygen in the blood. Patients with chronic kidney disease produce smaller amounts of EPO and are therefore often anemic. As a result, they look pale, are run-down and have difficulty breathing. For a good 20 years, this condition has been treated with synthetically produced EPO. This may cause blood pressure to rocket, however – “a dangerous side effect for kidney patients with cardiovascular problems,” explains Schäfer.

Professor Stefan Schäfer and Professor Frank Eitner (left to right) consider how they can develop new therapeutic options for patients with heart and kidney conditions that are precisely adapted to the needs of both organs.

Signal for Oxygen

The red blood cells are the carriers of oxygen in the blood, transporting the gas from the lungs to all tissues – and carrying carbon dioxide back again. Production of red blood cells is controlled by erythropoietin. This hormone is constantly being replenished by the body, as it cannot be stored.

Many Heart Patients Do not Receive Vital Medications because of their Side Effects

The Bayer researchers therefore now want to go about preventing anemia differently - with altitude training in tablet form. “Our active substance tricks the body into thinking it isn’t getting enough oxygen, as though it were at a training camp at an altitude of 4,000 meters in thin and therefore oxygen-poor air,” explains Eitner. In response, the body increases production of red blood cells, which improves the oxygen transport. The Bayer substance achieves this by intervening in a multilayered process. A protein called hypoxia-inducible factor – or HIF for short – is released by the human organism as soon as the oxygen content in tissue drops. When enough oxygen is present, the HIF is broken down and removed from the body. This process is initiated by the enzyme HIF prolyl hydroxylase (HIF-PH). When HIF remains stable, it activates the cellular production of EPO. “Our substance inhibits HIF-PH, so the kidney increases production of EPO, which ultimately leads to the production of the desired amount of red blood cells,” summarizes Schäfer.

Video: The New Active Ingredient for Patients with Kidney Disease and Anemia

The new active ingredient could also prevent one of the side effects of the current treatment with synthetic EPO: regular injections of EPO frequently lead to high blood pressure, a condition that further aggravates the burden of cardiovascular disease in kidney patients. Bayer’s researchers are therefore packaging their active substance in the form of tablets. “With a single tablet daily, EPO levels in the blood are raised only slightly, but constantly. This fits in with physiological processes considerably better than intermittent injections, which require high concentrations,” explains Schäfer. The oral administration also means a significant improvement of the quality of life for patients. Initial clinical studies with the new Bayer active substance revealed that this treatment was well tolerated within the therapeutic range. Clinical studies are currently starting worldwide to assess the safety and efficacy of the novel HIF-PH inhibitor in patients with anemia and chronic kidney disease.

We want to kill two birds with one stone by developing new molecules that are good for the heart and for the kidneys. Many patients suffer from both kidney and heart disease, and we aim to improve their lives.

Rack of samples: the urine samples are arranged neatly in rows for further testing. This is vital to ensure that the right results are allocated to each patient.

The researchers’ aim, however, is not just to make their new medicines easier for the organs to tolerate. A further goal is “to protect the heart and kidneys from abnormal tissue changes that often occur when organs are failing,” says Schäfer. In patients with these disorders, connective tissue proliferates, the organ stiffens and is no longer able to function properly, a process known in medicine as scarring or fibrosis. “Fibrosis has so far been unavoidable in patients with failing organs,” says Schäfer. The new Bayer substances now target the problem with new mechanisms of action: “We want to kill two birds with one stone by developing new molecules that are good for the heart and for the kidneys. Many patients suffer from both kidney and heart disease, and we aim to improve their lives,” continues Schäfer.

Interview: Luis Miguel Ruilope

“Similar Risk Factors Affect Both Organs“

Luis Miguel Ruilope is Associate Professor of Internal Medicine at Complutense University in Madrid, Spain, and Head of the Hypertension Unit at the Hospital 12 de Octubre. researchspoke to the specialist about the complexity of heart and kidney diseases.

How would you estimate the relevance of heart and kidney diseases?

Both organs are often affected by similar risk factors that lead to simultaneous development of cardiovascular (CV) and kidney disease. So chronic kidney disease is frequently seen in patients with CV disease. Also, its presence increases the risk of progression of CV disease, mainly atherosclerosis, with a higher likelihood of developing CV events such as a heart attack or even death and also of end-stage renal disease.

Why is it crucial to consider both heart and kidney when developing pharmaceuticals for one of the organs?

Appropriate medications can influence both the CV and the renal systems positively. Once chronic kidney diseases develop, new factors increase risk factors for both the CV and renal system and could in turn require new therapies – necessary considerations include, for example, drugs for anemia, the metabolism of the calcium-phosphate axis or more potent diuretics.

The MR antagonist, the HIF-PH inhibitor and the new substances for the treatment of progressive heart and kidney failure are products of the Wuppertal laboratories – developments that originated locally but are now set to go global. “We are currently building up a network for cooperation in the field of kidney research and development,” says Eitner. Such networks have already been established for other organs such as the lungs and the heart. Research atBayer HealthCare is structured namely by organ, not by disease: “We focus from the start on the patients and the organs that we want to treat,” explains Eitner. “That gives us an awareness, even at the early stages of development, of what people actually need.” And what kidney patients need is good protection for the heart and the kidneys.

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